Pharmacology

The first group, of which edrophonium is the example, consists

of quaternary alcohols. These agents reversibly bind electrostati-
cally and by hydrogen bonds to the active site, thus preventing

access of acetylcholine. The enzyme-inhibitor complex does not
involve a covalent bond and is correspondingly short-lived (on the
order of 2–10 minutes). The second group consists of carbamate
esters, eg, neostigmine and physostigmine. These agents undergo
a two-step hydrolysis sequence analogous to that described for
acetylcholine. However, the covalent bond of the carbamoylated
enzyme is considerably more resistant to the second (hydration)
process, and this step is correspondingly prolonged (on the order

of 30 minutes to 6 hours). The third group consists of the organo-
phosphates. These agents also undergo initial binding and hydro-
lysis by the enzyme, resulting in a phosphorylated active site. The

covalent phosphorus-enzyme bond is extremely stable and hydro-
lyzes in water at a very slow rate (hundreds of hours). After the

initial binding-hydrolysis step, the phosphorylated enzyme com-
plex may undergo a process called aging. This process apparently

involves the breaking of one of the oxygen-phosphorus bonds
of the inhibitor and further strengthens the phosphorus-enzyme

bond. The rate of aging varies with the particular organophos-
phate compound. For example, aging occurs within 10 minutes

with the chemical warfare agent soman, but as much as 48 hours
later with the drug VX. If given before aging has occurred, strong

nucleophiles like pralidoxime are able to break the phosphorus-
enzyme bond and can be used as “cholinesterase regenerator” drugs

for organophosphate insecticide poisoning (see Chapter 8). Once
aging has occurred, the enzyme-inhibitor complex is even more
stable and is more difficult to break, even with oxime regenerator
compounds.
The organophosphate inhibitors are sometimes referred to as
“irreversible” cholinesterase inhibitors, and edrophonium and the
carbamates are considered “reversible” inhibitors because of the
marked differences in duration of action. However, the molecular
mechanisms of action of the three groups do not support this
simplistic description.
B. Organ System Effects
The most prominent pharmacologic effects of cholinesterase
inhibitors are on the cardiovascular and gastrointestinal systems,
the eye, and the skeletal muscle neuromuscular junction (as
described in the Case Study). Because the primary action is to
amplify the actions of endogenous acetylcholine, the effects are
similar (but not always identical) to the effects of the direct-acting
cholinomimetic agonists.

1. Central nervous system—In low concentrations, the lipid-
soluble cholinesterase inhibitors cause diffuse activation on the

electroencephalogram and a subjective alerting response. In higher
concentrations, they cause generalized convulsions, which may be
followed by coma and respiratory arrest.
2. Eye, respiratory tract, gastrointestinal tract, urinary
tract—The effects of the cholinesterase inhibitors on these organ
systems, all of which are well innervated by the parasympathetic

nervous system, are qualitatively quite similar to the effects of the
direct-acting cholinomimetics (Table 7–3).
3. Cardiovascular system—The cholinesterase inhibitors can
increase activity in both sympathetic and parasympathetic ganglia

supplying the heart and at the acetylcholine receptors on neuroef-
fector cells (cardiac and vascular smooth muscles) that receive

cholinergic innervation.

In the heart, the effects on the parasympathetic limb pre-
dominate. Thus, cholinesterase inhibitors such as edrophonium,

physostigmine, or neostigmine mimic the effects of vagal nerve
activation on the heart. Negative chronotropic, dromotropic, and
inotropic effects are produced, and cardiac output falls. The fall
in cardiac output is attributable to bradycardia, decreased atrial
contractility, and some reduction in ventricular contractility. The

latter effect occurs as a result of prejunctional inhibition of nor-
epinephrine release as well as inhibition of postjunctional cellular

sympathetic effects.
Cholinesterase inhibitors have minimal effects by direct action
on vascular smooth muscle because most vascular beds lack
cholinergic innervation (coronary vasculature is an exception).
At moderate doses, cholinesterase inhibitors cause an increase in
systemic vascular resistance and blood pressure that is initiated at
sympathetic ganglia in the case of quaternary nitrogen compounds
and also at central sympathetic centers in the case of lipid-soluble

agents. Atropine, acting in the central and peripheral nervous sys-
tems, can prevent the increase of blood pressure and the increased

plasma norepinephrine.

The net cardiovascular effects of moderate doses of cholines-
terase inhibitors therefore consist of modest bradycardia, a fall in

cardiac output, and an increased vascular resistance that results in
a rise in blood pressure. (Thus, in patients with Alzheimer’s disease
who have hypertension, treatment with cholinesterase inhibitors

requires that blood pressure be monitored to adjust antihyperten-
sive therapy.) At high (toxic) doses of cholinesterase inhibitors,

marked bradycardia occurs, cardiac output decreases significantly,
and hypotension supervenes.
4. Neuromuscular junction—The cholinesterase inhibitors
have important therapeutic and toxic effects at the skeletal
muscle neuromuscular junction. Low (therapeutic) concentrations
moderately prolong and intensify the actions of physiologically
released acetylcholine. This increases the strength of contraction,
especially in muscles weakened by curare-like neuromuscular

blocking agents or by myasthenia gravis. At higher concentra-
tions, the accumulation of acetylcholine may result in fibrillation

of muscle fibers. Antidromic firing of the motor neuron may also
occur, resulting in fasciculations that involve an entire motor
unit. With marked inhibition of acetylcholinesterase, depolarizing
neuromuscular blockade occurs and that may be followed by a
phase of nondepolarizing blockade as seen with succinylcholine
(see Table 27–2 and Figure 27–7).

Some quaternary carbamate cholinesterase inhibitors, eg, neo-
stigmine and pyridostigmine, have an additional direct nicotinic

agonist effect at the neuromuscular junction. This may contribute
to the effectiveness of these agents as therapy for myasthenia.

Neuromuscular Junction
Myasthenia gravis is an autoimmune disease affecting skeletal
muscle neuromuscular junctions. In this disease, antibodies are
produced against the main immunogenic region found on α1
subunits of the nicotinic receptor-channel complex. Antibodies
are detected in 85% of myasthenic patients. The antibodies reduce
nicotinic receptor function by (1) cross-linking receptors, a process
that stimulates their internalization and degradation; (2) causing

lysis of the postsynaptic membrane; and (3) binding to the nico-
tinic receptor and inhibiting function. Frequent findings are ptosis,

diplopia, difficulty in speaking and swallowing, and extremity
weakness. Severe disease may affect all the muscles, including those
necessary for respiration. The disease resembles the neuromuscular
paralysis produced by d-tubocurarine and similar nondepolarizing
neuromuscular blocking drugs (see Chapter 27). Patients with
myasthenia are exquisitely sensitive to the action of curariform

drugs and other drugs that interfere with neuromuscular transmis-
sion, eg, aminoglycoside antibiotics.

Cholinesterase inhibitors—but not direct-acting acetylcho-
line receptor agonists—are extremely valuable as therapy for

myasthenia. Patients with ocular myasthenia may be treated with
cholinesterase inhibitors alone (Figure 7–4B). Patients having

more widespread muscle weakness are also treated with immuno-
suppressant drugs (steroids, cyclosporine, and azathioprine). In

some patients, the thymus gland is removed; very severely affected
patients may benefit from administration of immunoglobulins
and from plasmapheresis.

Edrophonium is sometimes used as a diagnostic test for myas-
thenia. A 2 mg dose is injected intravenously after baseline muscle

strength has been measured. If no reaction occurs after 45 seconds,
an additional 8 mg may be injected. If the patient has myasthenia
gravis, an improvement in muscle strength that lasts about 5 minutes
can usually be observed.
Clinical situations in which severe myasthenia (myasthenic

crisis) must be distinguished from excessive drug therapy (cho-
linergic crisis) usually occur in very ill myasthenic patients and

must be managed in hospital with adequate emergency support
systems (eg, mechanical ventilators) available. Edrophonium